KR20110009033A - Synthesis of iodixanol in methanol - Google Patents

Abstract

PURPOSE: A synthesis method of iodixanol in methanol is provided to ensure an environmentally friendly property using a low cost solvent and high enough yields and purity in the final product to make the manufacturing process of iodixanol economically feasible in an industrial scale. CONSTITUTION: 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide is dimerised in a temperature range of about 10 to about 20deg.C using methanol as solvent in a concentration of about 0.8 to about 2.0 ml solvent per g 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide in the presence of about 0.30 to about 0.36 mole equivalents of epichlorohydrin, and wherein the reaction solution has a pH value of about 11.5 to about 12.2.

Description

Synthesis of iodixanol in methanol {SYNTHESIS OF IODIXANOL IN METHANOL}

This application claims priority under 35 U.S.C. 119 (e) to US Provisional Application No. 61 / 227,095, filed Jul. 21, 2009, the entire disclosure of which is incorporated herein by reference.

The present invention relates to iodixanol (1,3-bis (acetamido) -N, N'-bis [3,5-bis (2,3-dihydroxypropylaminocarbonyl) -2,4,6- Triiodophenyl] -2-hydroxypropane), and more specifically 5-acetamido-N, N'-bis (2,3-dihydroxypropyl)-with methanol as a solvent. It relates to dimerisation of 2,4,6-triiodo-isophthalamide.

Iodo Dick sanol is a non-sheet Name of chemical agents in non-ionic X- ray contrast agent marketed under the trade name of the busy Park ^TM (Visipaque ^TM). BusyPark ^TM is one of the most widely used agents in diagnostic X-ray procedures and is prepared in large quantities.

Preparation of such nonionic X-ray contrast agents involves producing a chemical agent (hereinafter referred to as primary production) and then formulating it into a drug (hereinafter referred to as secondary production). Primary production of iodixanol involves multistage chemical synthesis and complete purification processes. For commercial drugs, it is important to supply drugs that must be effective and economical in primary production, and that meet the specifications, for example, as indicated in the US Pharmacopoeia.

Numerous methods are known for making iodixanol. These are all multistage chemical synthesis processes, and therefore the price of the final formulated product mainly depends on these processes. Therefore, it is important to optimize these processes for economic and environmental reasons.

In a preferred method for the preparation of iodixanol described in EP 108638, incorporated herein by reference, the final intermediate 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4 , 6-Trioiodo-isophthalamide (hereinafter “Compound A”) is reacted with a dimerizing agent such as epichlorohydrin to produce the drug (see Scheme I).

Scheme I

The reaction is generally carried out in non-aqueous solvent 2-methoxyethanol and usually results in the conversion of 40 to 60% of Compound A to iodixanol. The product contains a large amount of impurities and is usually purified by crystallization. Too large an impurity makes purification difficult, and crude iodixanol prepared by a synthetic chemical process is crystallized twice to achieve the desired purity. The process is time consuming and takes about 3 days for the first crystallization and about 2 days for the second crystallization. Thus, the crystallization process is very demanding in terms of time and equipment size, it will take several days to perform and is often an obstacle for industrial scale processes.

It is therefore desirable to find readily available low cost alternative solvents that can be used in the dimerization step and meet the criteria mentioned above.

WO 99/18054 describes a method for crystallizing iodixanol in which a solvent mixture comprising methanol and propan-2-ol is used in the examples. While a significant number of other common solvents have been suggested, many of them are not feasible on an industrial scale and there is no suggestion on how to perform crystallization in terms of proportions or process parameters.

US 5349085 describes a process for the preparation of iodixanol using water as a solvent at room temperature with epichlorohydrin as a dimerizing agent.

WO 98/23296 refers to the synthesis of iodixanol and refers to solvents available in the same general method as in WO 99/18054, including alcohols.

Surprisingly, it was found that methanol can be used as a solvent in the dimerization step of Compound A on an industrial scale and will meet the requirements listed above.

The present invention provides a method for large scale dimerization of 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide of iodixanolo do.

Accordingly, the present invention provides a 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isoph, in the temperature range of about 10 to about 20 ° C. 5-acetamido-N, N'-bis (2) in the presence of about 0.30 to about 0.36 molar equivalents of epichlorohydrin using methanol as the solvent at a concentration of about 0.8 to about 2.0 ml solvent per g of deamide A method of dimerizing, 3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide is provided wherein the reaction solution has a pH value of about 11.5 to about 12.2.

The method uses environmentally friendly low cost solvents and provides high yields and purity in the final product to make the manufacturing process of iodixanol economically feasible on an industrial scale.

Crude iodixanol is obtained from a process known in the art, for example the dimerization process depicted in Scheme I above. The dimerization step itself can be carried out, for example using epichlorohydrin as the dimerization agent, as described in EP 108638 and WO 98/23296. This reaction is generally carried out in non-aqueous solvent 2-methoxyethanol and generally results in the conversion of 40 to 60% of Compound A to iodixanol.

To date, methanol has been suggested as a possible alternative solvent in the dimerization step for the preparation of iodixanol, but no literature indicates that the use of methanol is feasible on an industrial scale. Thus, other solvents, in particular 2-methoxyethanol, have been used in large scale production of iodixanol.

As described above, dimerization generally results in a conversion of 40-60% of Compound A. However, the product contains a large amount of impurities and requires the execution of expensive post-treatment procedures, for example several crystallizations.

The most important impurity in the reaction with regard to the aftertreatment results is the so-called backpeak. The term means residence time in reverse phase HPLC, with a back peak having a residence time slightly longer than the residence time of iodixanol itself. Most back peaks are either trimers or O-alkylated dimers. Two examples are given below:

Other important by-products are for example iopentol, iohexol and N-acetyl cyclized iodixanol, with the structural formulas shown below. Iohexol and iopentol, even when present in several weight percent, are fairly easy to remove in subsequent crystallization of iodixanol.

The typical selectivity required to be able to perform an economically feasible aftertreatment and to obtain the required product quality is 2% of the amount of back peak at a conversion rate of 55-60% of Compound A converted to iodixanol. It should not exceed. It is further advantageous if the back peak does not exceed 1.4% at this conversion rate.

Surprisingly, it has been found that under certain conditions, the dimerization step can be carried out using methanol as the solvent, resulting in a product that meets the requirements for making the total process of preparing iodixanol feasible.

Thus, the present invention provides a 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isoph, at temperatures ranging from about 10 to about 20 ° C. 5-acetamido-N, N'-bis (b) in the presence of about 0.30 to about 0.36 molar equivalents of epichlorohydrin using methanol as the solvent at a concentration of about 0.8 to about 2.0 ml solvent per g of deamide. A method of dimerization of 2,3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide is provided, wherein the reaction solution has a pH value of about 11.5 to about 12.2.

The process according to the invention is carried out at a solvent concentration of about 0.8 to about 2.0 ml, more preferably about 0.8 to about 1.0 and most preferably about 0.80 to about 0.85 ml per g of Compound A.

The temperature during dimerization should range from about 10 to about 20 ° C, with about 10 ° C being most preferred. The temperature may be kept constant during dimerization or may vary within a certain range, preferably the temperature is lowered throughout the dimerization.

Dimerization agents used in the present invention are epichlorohydrin added in about 0.3 to about 0.36 molar equivalents.

The pH value in the reaction solution is about 11.5 to about 12.2. The pH value can preferably be changed during dimerization to have a higher value at the beginning than at the end of the dimerization.

The base used to raise the pH value of the reaction solution can be any suitable base. Preferably the base is sodium hydroxide (NaOH) or potassium hydroxide (KOH), with sodium hydroxide being most preferred.

For further titration of the pH value of the reaction solution, any suitable acid may be used, preferably concentrated hydrochloric acid (HCl).

The dimerization step will be allowed to proceed for several hours, preferably a reaction time of 12 to 48 hours, and particularly preferably 24 to 48 hours. The reaction can be terminated by quenching with any acid, preferably hydrochloric acid. The reaction is monitored, for example by HPLC, to determine the appropriate time point at which quenching should occur.

The present invention further describes the following examples and should not be construed to limit the invention to the scope of the specific procedures or products described in the examples.

Example

Example  One

5-acetylamino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide (Compound A) (201.5 g, 0.268 mol) was methanol at 45 ° C. (168 mL, 0.84 mL / g Compound A) and sodium hydroxide (13.92 g, 0.348 mol, 1.30 equiv) solution. The mixture was cooled to 10 ° C. and concentrated hydrochloric acid (16 mL, 0.192 moles, 0.72 equiv) was added followed by the addition of epichlorohydrin (7.43 g, 0.080 moles, 0.30 equiv) in one portion. After 48 hours HPLC analysis showed the following composition: 46.8% iodixanol, 46.3% Compound A, 1.09% back peak, 0.06% N-acetyl cyclized iodixanol, 3.80% iohexol and 1.23% iopentol.

Example  2

5-acetylamino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide (Compound A) (201.5 g, 0.268 mol) was methanol at 45 ° C. (168 mL, 0.84 mL / g Compound A) and sodium hydroxide (13.92 g, 0.348 mol, 1.30 equiv) solution. The mixture was cooled to 10 ° C. and concentrated hydrochloric acid (17 mL, 0.204 mol, 0.76 equiv) was added followed by the addition of epichlorohydrin (8.92 g, 0.096 mol, 0.36 equiv) in one portion. After 48 hours HPLC analysis showed the following composition: 50.4% iodixanol, 40.3% compound A, 1.37% back peak, 0.06% N-acetyl cyclized iodixanol, 5.75% iohexol and 1.37% iopentol.

Example  3

5-acetylamino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide (Compound A) (201.5 g, 0.268 mol) was methanol at 45 ° C. (200 mL, 1.00 mL / g Compound A) and sodium hydroxide (13.92 g, 0.348 mol, 1.30 equiv) solution. The mixture was cooled to 20 ° C. and concentrated hydrochloric acid (17 mL, 0.204 mol, 0.76 equiv) was added followed by the addition of epichlorohydrin (8.92 g, 0.096 mol, 0.36 equiv) in one portion. After 48 hours HPLC analysis showed the following composition: 52.1% iodixanol, 36.2% Compound A, 1.42% back peak, 0.20% N-acetyl cyclized iodixanol, 7.42% iohexol and 2.06% iopentol.

Example  4

5-acetylamino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide (Compound A) (201.5 g, 0.268 mol) was methanol at 45 ° C. (168 mL, 0.84 mL / g Compound A) and sodium hydroxide (13.92 g, 0.348 mol, 1.30 equiv) solution. The mixture was cooled to 15 ° C. and concentrated hydrochloric acid (17 mL, 0.204 mol, 0.76 equiv) was added followed by the addition of epichlorohydrin (8.17 g, 0.088 mol, 0.33 equiv) in one portion. After 48 hours HPLC analysis showed the following composition: 50.9% iodixanol, 39.1% Compound A, 1.40% back peak, 0.13% N-acetyl cyclic iodixanol, 7.00% iohexol and 1.59% iopentol.

All patents, articles, publications and other documents discussed and / or cited above are hereby incorporated by reference.

Claims (1)

The reaction solution has a pH value of about 11.5 to about 12.2 and at temperatures ranging from about 10 to about 20 ° C., 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2, 5-acetamido in the presence of about 0.30 to about 0.36 molar equivalents of epichlorohydrin using methanol as the solvent at a concentration of about 0.8 to about 2.0 ml solvent per gram of 4,6-triiodo-isophthalamide. A method of dimerizing -N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide.